Helicobacter pylori (Hp) are one of the most genetically diverse of bacterial species. Our preliminary DNA-based phylogenetic analyses showed that genotypes of Hp in Spain differ from those in East Asia, and that genotypes of Hp from Peruvians in Lima are mostly Spanish-like. The studies proposed for this grant period have four main specific aims. AIM 1. To better understand Hp genetic diversity and genome evolution. We will extend current phylogenetic studies to Hp strains from other Amerind people in Latin America, to test predictions that most such Hp strains will also be Spanish-like at most loci. Any Hp population found to be rich in alleles unlike those of Spain will be examined further. Hp from elsewhere in Europe, Asia and Africa will also be studied (i) to better understand Hp population genetic structure worldwide, (ii) test predictions that Hp gene pools in Japan and Spain represent subsets of more genetically diverse East Asian and European gene pools, respectively. AIM 2. To identify naturally occurring allele differences that affect fitness and understand their basis. We will test the generality of our finding that East Asian-type alleles of the comB9 gene are abundant in Hp from Amerinds in Lima, and test if this reflects selection. More generally, additional cases of unusual abundance of particular alleles or genes will be investigated to identify bacterial traits important in specificity of host interaction. Effects on fitness of candidate genes or alleles will be examined using genetically manipulated rodent-adapted Hp strains and mouse and gerbil infection models. AIM 3. To examine Hp evolutionary dynamics within family units, Hp strains from parents and children in individual Peruvian families will be genotyped to gain insights into relatedness, intrafamilial vs. community transmission, and mutation, recombination, and selection on Hp in societies where overall risks of infection are high. AIM 4. To detect transmission between communities, mixed infection, and potential for recombination. Hp from Japanese Peruvians will be genotyped to detect (i) retention of ancestral Japanese-type genes, vs. community acquisition of putative Native Peruvian (Spanish-type) strains; (ii) mixed infections, especially involving strains of different ethnic origins, (iii) extent of recombination in a brief time frame, and (iv) selection for particular genes or alleles.